The most widely accepted hypothesis for the pathogenesis of schizophrenia is that schizophrenia is related to increased dopamine (DA) function. However, over 20% of schizophrenic patients are refractory to treatment with conventional, antidopaminergic drugs. Clozapine is the only compound proven to be effective in this group of treatment refractory schizophrenics. Significantly, its clinical superiority may not be related to DA(2) systems, suggesting that DA dysfunction may not be a pathogenetic mechanism in treatment refractory schizophrenia. Clozapine is, in contrast to conventional neuroleptics, a potent serotonin (5HT) antagonist, reducing 5HT receptor sensitivity after chronic administration. Whether clozapine is clinically superior due to its 5HT antagonism has not been studied, despite evidence that blockade of 5HT receptors has beneficial effects in schizophrenia. This study hypothesizes that increased 5HT function is a pathogenetic mechanism in some treatment refractory schizophrenic patients. Clozapine is hypothesized to be effective in these patients, because it, unlike haloperidol, reduces 5HT receptor sensitivity after chronic administration. To test this hypothesis, the 5HT receptor agonist, m- chlorophenylpiperazine (MCPP) will be used as a probe to examine 5HT function. Behavioral, neuroendocrine and other physiological responses to MCPP will be measured in 80 schizophrenic patients and 20 normal subjects after a four week drug-free period. Following this assessment of 5HT function, all patients will e treated with haloperidol 20 mg/day for 5 weeks. The MCPP test will be repeated during the 5th week of haloperidol treatment. After this treatment episode, patients will be classified as responders and non-responders to haloperidol. Non-responders (expected to be about 60 in our patient population) will then be treated with clozapine 500 mg/day for 5 weeks. The MCPP challenge test will be repeated after 5 weeks of clozapine treatment. Patients will then be classified as responders and non-responders to clozapine. Resolving the issue whether clozapine's clinical superiority is related to its effects on 5HT systems will contribute to understanding the pathogenesis of (treatment refractory) schizophrenia and may lead to further development of compounds with pronounced (or selective) effects on 5HT systems for use in certain schizophrenic patients.